Alcohol abuse by current military personnel and Veterans is a significant health concern. Enlisted personnel returning from deployment are often young enough that brain maturation and refinement processes are still ongoing. Given the escalation of drinking and stress-related risk factors in this population, it is crucial to understand how alcohol affects the brain during this tme period and later on in life. To investigate the neurobiological processes that are affected by alcohol abuse during this critical period of brain development, we replicate the blood alcohol levels seen in humans during alcohol binges by use of a chronic intermittent ethanol (CIE) paradigm. Our lab has previously shown that rats exposed to this ethanol paradigm during late stage brain development undergo changes in brain physiology that manifest as impaired learning and memory even into adulthood. Until recently, the field has primarily focused on alcohol's specific effects on neurons and neuronal signaling. Here, we instead propose to elucidate the contributions of the non-neuronal glial cells, including astrocytes and microglia, as a novel approach to understand the cellular mechanisms that underlie synaptic dysfunction resulting from repeated ethanol exposure. Astrocytes, in particular, play a critical role in synaps formation, neuronal maintenance, and synaptic repair after injury through the release of astrocyte- secreted factors. However, when astrocyte signaling goes awry, the resulting stress placed on neurons contributes to the pathology of disease states, such as epilepsy and neuropathic pain. Using our CIE paradigm in rats, we now have evidence that some of these astrocyte-signaling factors and their receptors involved in synapse formation are chronically upregulated in the hippocampus brain region into adulthood, well after the acute effects of alcohol exposure have subsided. This upregulation corresponds with disruptions in hippocampal synaptic structure and function, highlighted by selective deficits in a spatial memory task. These results suggest that the upregulation in astrocyte-secreted factors may contribute to the observed structural and functional neuronal changes observed after CIE, leading us to hypothesize that changes in astrocyte function during CIE contribute to these observed synaptic deficits. Intriguingly, pharmacologically inhibiting the interaction between one of these secreted factors and its neuronal receptor during the acute response to CIE prevented the upregulation of this receptor at later time points, strengthening our hypothesis that changes in astrocyte function during CIE are driving the protracted synaptic deficits. Astrocytes and microglia have also been known to initiate and respond to inflammatory signaling cascades induced by excessive alcohol exposure, but here we propose to investigate whether the inflammation is linked to the upregulation of glial signaling factors and the disruption of synaptic structure and function observed after CIE. In summary, this proposed work uses a novel cellular approach to unravel the mechanisms of brain injury and dysfunction that occur after alcohol abuse, implicating astrocytes as potential targets for innovative therapeutic strategies in line with the VA mission.